Novel Method of Pancreatic Islet Transplantation Into the Omentum

Despite continuing progress in pharmacological insulin substitution, insulin administration and monitoring of glucose levels, type 1 diabetes has been still associated with specific late organ complications. While the main pathophysiological factor for their development is chronic hyperglycemia, the critical limiting factor for achieving normal or near-normal blood glucose levels remains to be the risk of hypoglycemia. Stable glucose levels near the normal range maintained without the fear of low excursions have been so far achieved only by organ pancreas or islet transplantation, however at the cost of surgical procedure and lifelong immunosuppression to prevent rejection of the graft and recurrence of the autoimmune process. Transplantation is therefore considered only in patients with serious complications of diabetes in whom the quality of life is unacceptable. This group now includes also subjects with hypoglycemia unawareness syndrome complicated by severe life-threatening hypoglycemic episodes, in whom qualified medical treatment including available technological support failed.

Most islet transplantations are currently performed by a minimally invasive technique via infusion into the portal vein with subsequent seeding in the liver. This way of implantation, however, still bares significant risks of bleeding during the percutaneous portal catheterization or portal thrombosis. Several other factors suggest that the liver may not be the optimal site for islet infusion.

The optimal place for the islet graft should be based on minimally-invasive transplant procedure, allow to use relatively large volumes of tissue (e.g., for low purity preparations), enable noninvasive longitudinal monitoring and access for biopsy. Portal blood drainage would be preferable to reproduce physiological metabolic responses.

These requirements might fulfill implantation into the omentum as it represents a large, well-vascularized surface and the capillary beds lie directly under the mesothelium. Omentum is easily accessible and venous blood is drained into the portal system (as from the native islets). A technique for human islet transplantation into the omentum has recently been developed in the Diabetes Research Institute in Miami under the leadership of C. Ricordi. The Miami group demonstrated, that the islets re-suspended in either donor or autologous plasma and distributed in the omental pouch did not stick together and allowed regular distribution on the omentum surface. Better cell adherence was achieved by addition of clinical-grade human thrombin which supported development of a biocompatible, degradable gel containing the islet graft. This technology, which does not include any ex vivo biological manipulation with the islet cells (and does not therefore fall under the term "modern therapy" in EU], does not require the use of any officially yet not approved drugs or medical instruments, could be directly applied in a pilot clinical experiment and help to speed up the development of a more efficient and safer method for islet transplantation in type 1 diabetic subjects.

The investigators propose to conduct a pilot clinical study in 10 type 1 diabetic subjects suffering from hypoglycemia unawareness syndrome and episodes of severe hypoglycemia, in which therapy with transplantation of allogeneic pancreatic islets would be indicated according to current criteria at the Institute for Clinical and Experimental Medicine (IKEM). Pancreatic islets will be isolated and prepared for transplantation using the established labora¬tory technique with minor modifications corresponding to latest knowledge. In contrast to present routine, the islet preparation will not be administered percutaneously into the portal vein but will be placed on the surface of an omental pouch using a (mini) laparoscopic approach. Cell adherence will be achieved by addition of clinical-grade human thrombin that reacts with plasma to create a biocompatible, degradable gel containing the islet graft. Study procedures will be based on the protocol developed by the DRI with modifications resulting from experience of the applicant´s team and equipment of local facilities.